Reprogramming the pancreatic tumor microenvironment with immunotherapy

 描述（由申请人提供）：癌症免疫疗法是过去十年中最大的突破之一。然而，迄今为止，单药免疫疗法的成功仅限于少数实体恶性肿瘤，包括黑色素瘤、肾细胞癌和非小细胞肺癌。对检查点抑制剂有反应的癌症与胰腺导管腺癌（PDA）等没有反应的癌症之间的一个区别是肿瘤微环境（TME）的免疫状态。PDA，像许多其他实体恶性肿瘤，被认为是“非免疫原性”。我们最近报道，PDA肿瘤切除后两周的单次新辅助剂量的粒细胞-巨噬细胞集落刺激因子（GM-CSF）分泌PDA疫苗（GVAX）诱导形成新的免疫活性的三级淋巴聚集体，有组织的淋巴结样结构，没有观察到从未接种疫苗的患者切除的肿瘤组织。这项先前的研究首次表明，基于疫苗的免疫疗法可以将免疫静止的TME重新编程为免疫活性的TME。然而，PDA TME中的活化T细胞分泌干扰素-γ，其进而上调PD-1/PD-L1。因此，我们假设用GVAX治疗引发PDA TME用于抗PD-1/PD-L1靶向治疗。支持这一假设，我们的临床前研究表明，将抗PD-1或PD-L1抗体与疫苗结合可提高效应T细胞浸润PDA的频率和PDA荷瘤小鼠的治愈率。为了进一步检验这一假设，我们将招募50名患有可切除PDA的患者并随机分配到一项2组临床试验中，接受单独使用GVAX加环磷酰胺（Cy）或与抗PD-1抗体（纳武单抗）联合使用的一种新辅助治疗。手术切除PDA前两周，随后进行五种额外的辅助免疫治疗。我们将比较治疗前穿刺活检的PDA标本和手术切除的肿瘤，并评估本临床试验的主要终点（疫苗诱导的淋巴聚集体中的IL 17 A表达）和次要终点（安全性、无病生存期和总生存期）。我们 将评估抗PD-1抗体阻断联合Cy/GVAX对PD-L1/PD-1相关通路、疫苗诱导的免疫调节特征以及外周和肿瘤内抗原特异性T细胞应答的影响。这些结果预计将确定调节PD-1/PD-L1通路在PDA TME中的作用，以确定可能补偿PD-1阻断的替代调节通路，并确定PDA TME内免疫应答的特征。如果组合治疗组显示出淋巴聚集体中增强的IL 17 A表达和/或比单独的Cy/GVAX更好的存活率，我们将在随机研究中将两个治疗组与标准护理进行比较，样本量足以估计临床疗效的改善。

 DESCRIPTION (provided by applicant): Cancer immunotherapy is among the biggest breakthroughs in the last decade. However, the success of single agent immunotherapy has so far been limited to a few solid malignancies, including melanoma, renal cell carcinoma, and non-small cell lung cancer. One difference between cancers that have responded to checkpoint inhibitors and cancers like pancreatic ductal adenocarcinoma (PDA) that have not is the immune status of the tumor microenvironment (TME). PDA, like many other solid malignancies, was considered to be "non-immunogenic". We recently reported that PDA tumors resected just two weeks following a single neoadjuvant dose of a granulocyte-macrophage colony stimulating factor (GM-CSF) secreting PDA vaccine (GVAX) induces the formation of novel immunologically active tertiary lymphoid aggregates, organized lymph node-like structures that are not observed in tumor tissue resected from unvaccinated patients. This prior study showed for the first time that a vaccine-based immunotherapy can reprogram an immunologically quiescent TME into an immunologically active TME. However, activated T cells in the PDA TME secrete interferon-γ, which in turn upregulates PD-1/PD-L1. Thus, we hypothesize that treatment with GVAX primes the PDA TME for anti-PD-1/PD-L1-targeted therapy. Supporting this hypothesis, our preclinical studies showed that combining anti-PD-1 or PD-L1 antibodies with vaccines enhances the frequency of effector T cells infiltrating PDAs and the cure rate in PDA tumor-bearing mice. To further test this hypothesis, we will enroll and randomize 50 patients with resectable PDAs to a 2-arm clinical trial to receive either one neoadjuvant treatment with GVAX plus Cytoxan (Cy) alone or in combination with an anti-PD-1 antibody (nivolumab) two weeks prior to surgical resection of their PDAs, followed by five additional adjuvant immunotherapies. We will compare PDA specimens from a pre-treatment core biopsy and the surgically resected tumors and evaluate primary endpoint (IL17A expression in vaccine-induced lymphoid aggregates) and secondary endpoints (safety, disease free survival and overall survival) of this clinical trial. We will assess the effects of anti-PD-1 antibody blockade in combination with Cy/GVAX on the PD-L1/PD-1 associated pathways, vaccine-induced immune regulatory signatures, and peripheral and intratumoral antigen specific T cell responses. The results are expected to determine the role of modulating the PD-1/PD-L1 pathway in the PDA TME, to identify alternate regulatory pathways that may compensate for PD-1 blockade, and to identify signatures of immune response within the PDA TME. If the combinatorial treatment arm demonstrates enhanced IL17A expression in lymphoid aggregates and/or better survival than Cy/GVAX alone, we will compare the two treatment arms against standard of care in a randomized study with a sample size adequate to estimate an improvement in clinical efficacy.